Enoxaparin

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Abstract
Enoxaparin (enoxaparin sodium) is a low molecular weight heparin (LMWH) that is widely used in the prevention of deep venous thrombosis and pulmonary embolism in patients undergoing orthopaedic or general surgery. Its efficacy in these indications has led to study of its use in patients with coronary artery disease, particularly those with unstable angina, who have a high risk of myocardial infarction and death. A double-blind multicentre study [ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events)] showed that subcutaneous enoxaparin was more effective than intravenous unfractionated heparin (UFH) in reducing the incidence of the composite end-point of death, myocardial infarction or recurrent angina after 14 days in 3171 patients with recent-onset resting angina (i.e. unstable angina). There were no statistically significant between-group differences for the secondary end-point of death or myocardial infarction. Preliminary reports of long term follow-up data indicate that the clinical benefit of enoxaparin over UFH is maintained after 1 year. The only significant difference in tolerability between enoxaparin and UFH in ESSENCE was for minor haemorrhage (mostly injection-site ecchymosis), which was more common with the LMWH. Prospective pharmacoeconomic substudies of the ESSENCE trial suggest that total medical costs (including those for subsequent revascularisation procedures) for enoxaparin treatment are lower than those for UFH. The ESSENCE study is the first double-blind trial to show that a LMWH is more effective than UFH in patients with unstable angina. The superiority of enoxaparin was attributable mainly to its effects on recurrent angina. The level of anticoagulation achieved in the UFH group raises a number of issues which might have affected the apparent relative efficacy of enoxaparin and UFH. Preliminary data suggest that enoxaparin is at least as effective as UFH in reducing the incidence of subsequent cardiac events in patients receiving throm-bolysis for acute myocardial infarction, and a randomised comparison with no additional treatment (other than aspirin) has demonstrated its efficacy in this indication. Enoxaparin has been ineffective in preventing restenosis after angioplasty Conclusions: The ESSENCE study has shown that enoxaparin is more effective than UFH in patients with unstable angina. Although clarification of some methodological issues would be beneficial, the available efficacy data, together with the practical advantages of LMWHs in general, suggest that enoxaparin is an effective and convenient means of treating unstable angina and should provide cost savings compared with UFH. Enoxaparin (enoxaparin sodium) is a low molecular weight heparin (LMWH) which contains polysaccharide chains with an average molecular weight of about 4 to 5kD [compared with about 12 to 15kD for unfractionated heparin (UFH)]. Like UFH, enoxaparin achieves its anticoagulant effects primarily by binding to antithrombin III. This increases the inhibitory activity of the latter molecule against procoagulatory serine proteases. As aresult, enoxaparin indirectly inhibits the prothrombinase-mediated conversion of prothrombin to thrombin and the thrombin-mediated conversion of fibrinogen to fibrin, thus preventing clot formation. In common with other LMWHs, enoxaparin has a higher ratio of anti-factor Xa activity to anti-factor IIa activity (2.7: 1) than UFH (1: 1). Platelet-dependent thrombin generation and platelet prothrombinase activity were inhibited in plasma from patients with unstable angina who had received enoxaparin. Enoxaparin had little effect on platelets in vivo in patients with unstable angina and ex vivo in plasma from healthy volunteers; in contrast, UFH stimulated platelet activation in vivo and increased platelet aggregability ex vivo. Enoxaparin is rapidly absorbed after subcutaneous administration and has higher bioavailability than UFH (91 vs 29%). A linear dose relationship is evident for anti-factor Xa activity and the area under the anti-factor Xa activity-time curve over the dose range 20 to 80mg. Enoxaparin shows minimal binding to plasma proteins. The sustained biological activity of enoxaparin, like that of other LMWHs, allows less frequent administration than that required for UFH. Elimination of enoxaparin is predominantly renal and is nonsaturable. A large double-blind multicentre study, ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events), compared the efficacy of subcutaneous enoxaparin 1 mg/kg every 12 hours with that of intravenous UFH [adjusted according to activated partial thromboplastin time (aPTT)] in 3171 patients with recent-onset resting angina. Analysis of the triple composite end-point of death, myocardial infarction or recurrent angina after 14 days (the primary end-point) revealed a statistically significant benefit favouring enoxaparin over UFH (16.6 vs 19.8%, 16.2% relative risk reduction). This was mainly due to a lower incidence of recurrent angina in the enoxaparin group (12.9 vs 15.5%). Nonsignificant trends favouring enoxaparin over UFH were evident for the double composite end-point of death or myocardial infarction (at 14 and 30 days) and for the single end-points of death (after 30 days) and myocardial infarction (after 14 and 30 days). Enoxaparin recipients also had significantly less need for coronary artery revascularisation than UFH recipients after 30 days (27.0vs 32.2%). Enoxaparin was significantly more effective than UFH after 1 year according to preliminary reporting of follow-up data for 2915 patients in the ESSENCE study (quantitative statistical data are not yet available). The triple end-point of death, myocardial infarction or recurrent angina was significantly less common in enoxaparin recipients than in UFH-treated patients (32 vs 35.7%), as was death or myocardial infarction (11.5 vs 13.5%). A prospective economic substudy of resource utilisation and related medical costs for the 923 US patients in the ESSENCE trial indicated that hospital costs, physician fees and total costs at 30 days were significantly lower with enoxaparin than with UFH ($US1172 cost saving for treatment of the total population). A cost saving for enoxaparin compared with UFH was also apparent for the 191 UK patients in the ESSENCE study. The total cost of treating 100 patients with enoxaparin was about £2367 lower than that for UFH. Preliminary data from a randomised study in 300 patients who had received thrombolysis for acute myocardial infarction suggest that enoxaparin is at least as effective as UFH (both administered for 4 days) in preventing cardiac events. The total incidence of cardiac events at 3-month follow-up was significantly lower in the enoxaparin group than in the UFH group (26 vs 36%), as was reinfarction in the 48 hours after drug discontinuation (2 vs 7%). The incidence of individual cardiac events did not differ significantly between groups. Enoxaparin was more effective than no additional treatment in a nonblind study in patients with acute myocardial infarction who had been treated for 5 days previously with streptokinase and UFH (all patients received aspirin). Compared with the control group, patients receiving aspirin and enoxaparin for 25 days had significantly less reinfarction (4.6 vs 21.6%) and a lower total incidence of cardiac events (14 vs 43%) to 6 months. Two large randomised studies have shown that enoxaparin is not effective in preventing restenosis after angioplasty. As with other LMWHs, the most common adverse event associated with enoxaparin is bleeding. However, major haemorrhage occurred in only 1.9 to 6.5% of 2143 patients with coronary artery disease who received enoxaparin 1 mg/kg twice daily or 40mg once daily in 3 large clinical trials. In the ESSENCE study, total haemorrhagic complications were significantly more common in patients receiving subcutaneous enoxaparin 1 mg/kg twice daily (18.4%) than in those receiving intravenous UFH (bolus plus continuous infusion adjusted to aPTT) [14.2%]. This reflected a significantly higher incidence of minor bleeding (mainly injection site ecchymosis, as expected with subcutaneous administration) in the enoxaparin group (11.9 vs 7.2%). Major bleeding did not differ significantly between groups. Nonhaemorrhagic adverse events are generally infrequent in enoxaparin recipients. Fever, oedema, hypochromic anaemia, nausea, pain and confusion were each reported by 2 to 6% of 786 patients with thrombotic disease who received enoxaparin 30mg twice daily in US clinical trials. Patients with unstable angina or non-Q wave myocardial infarction should receive enoxaparin 1 mg/kg subcutaneously every 12 hours (in addition to aspirin) for at least 2 days. Treatment should be continued until clinical stabilisation (typically up to 8 days).